BRPI0907228B1 - THIENOPYRIDAZINE COMPOUNDS, THEIR PREPARATIONS, PHARMACEUTICAL COMPOSITIONS AND USES - Google Patents

Abstract

thienopyridazine compounds, preparations thereof, pharmaceutical compositions and uses the present invention relates to thienopyridazine compounds of formula (I), their pharmaceutically acceptable salts or hydrates, where r1 and r2 are independently h or c1-4 alkyl, r3 is a ring 5- or 6-membered saturated or unsaturated containing n, s or o, or optical isomers thereof, R4 is a halophenyl monosubstituted or disubstituted at any position. the present invention provides the processes for preparing these compounds, pharmaceutical compositions containing these compounds and the uses of these compounds, particularly in the treatment of cancer. (i)

Description

FIELD OF THE INVENTION

[001] The present invention relates to pharmaceutical chemistry, in particular relates to thienopyridazine compounds, their preparations and pharmaceutical compositions containing them and their uses.

BACKGROUND OF THE INVENTION

[002] Cancer is a threat to human health, and most cancers in humans are caused by external environmental factors. Every year, at least 5 million people die from cancer around the world. The cure rate is still low, although some treatment methods are currently available to cure patients, such as surgery, radiation therapy, chemotherapy and so on. Using pharmaceutical chemicals to prevent and treat cancers is currently one of the most effective methods.

[003] It has been found that thienopyridazine compounds or compounds of their thieno analogues have antitumor activities.

[004] F. Hoffman-La Roche AG discloses a thienopyridazine as an IKK inhibitor in WO2005105808.

Amgen Inc. of the USA discloses a thienopyridazine compound as a p38 protease tyrosine kinase inhibitor in WO2007124181.

Smithkline Beecham Corporation has disclosed a 2-ureidothiophene compound in WO03029241 and a 3-ureidothiophene compound in WO03028731, which are similar to thienopyridazine compounds as CHK1 inhibitors. AstraZeneca AB discloses a modified 3-ureidothiophene compound as a CHK1 inhibitor in WO 2005066163.

[007] Pharmaceutical chemicals to prevent and treat cancers currently include inhibitors of receptor tyrosine kinases and non-receptor tyrosine kinases, and their targets include VEGFR, EGFR, HER2, SRC, JAK and TEK; and also include inhibitors of threonine serine kinases and their targets include MEK, JNK, c-MET, AKT, PIM, TIE, PLK and so on. The compounds of the present invention are inhibitors of cancers and protein kinases including the cell cycle Kinase CHK1/CHK2 Checkpoint.

[008] It has been found, from research to regulate cell cycle checkpoints, that shutting down CHK1 expression can reverse the drug resistance of cancer cells and thus increase the sensitivities of tumor cells to damage therapy. DNA, and dramatically increase the activities of anticancer pharmaceuticals. In addition, tumor-selective pharmaceuticals can be obtained through most tumors that have p53 mutation characteristics to eliminate the G1/S checkpoint. The present invention provides a novel thienopyridazine compound, as inhibitors of novel tumor protein kinases associated with growth factors (including CHK1, CHK2), which not only have antitumor actions, but can also enhance the antitumor efficacy of other antitumor pharmaceuticals .

SUMMARY OF THE INVENTION

[009] According to the present invention, the applicant has discovered new compounds that have anti-proliferative activities (for example, anti-cancer activities) and thus used for the treatment of humans and animals. The present invention also relates to processes for obtaining said compounds, pharmaceutical compositions containing them, and their uses in the preparation of pharmaceuticals for use in the production of antiproliferative effects in animals, as in man.

[010] The present invention includes pharmaceutically acceptable salts or prodrugs of such compounds, and applicant also provides pharmaceutical compositions and methods of using such compounds for the treatment of cancer, in accordance with the present invention.

[011] Such properties of the compounds of the present invention are expected to be of useful value for the treatments of diseases associated with cell cycle stagnation and cell proliferation as follows: cancer (solid tumor and leukemia), fibroproliferative and differential diseases, psoriasis, rheumatoid arthritis , Kaposi's sarcoma, chronic and acute nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and eye diseases with retinal vessel proliferation.

R3 é um anel de 5 ou 6 membros saturado ou insaturado contendo N, S ou O, e um isômero ótico a partir dele; R4 é uma halofenila monossubstituída or dissubstituída em qualquer posição.[012] According to one aspect of the present invention, compounds of formula (I) or pharmaceutically acceptable salts or hydrates thereof are provided, wherein, R 1 and R 2 are independently H or C 1-4 alkyls;

R3 is a 5- or 6-membered saturated or unsaturated ring containing N, S or O, and an optical isomer therefrom; R4 is a halophenyl monosubstituted or disubstituted at any position.

[013] Preferably, R1=R2=H.

[014] Preferably, R3 is a 6-membered saturated ring containing N, S or O, and their optical isomers.

[015] Preferably, R3 is hexahydropyridyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolidinyl, tetrahydrofuranyl, or tetrahydrothienyl, and its optical isomers.

[016] Preferably, R3 is hexahydropyridinyl, and its optical isomers.

[017] Preferably, R4 is a monosubstituted halophenyl.

, onde X representa F, Cl, Br, I.[018] Preferably, R4 is

, where X represents F, Cl, Br, I.

2-(4-clorofenil)-4-(3-piperidinometil)-tieno [2,3-d] piridazinil-7- formamida;

2-(4-bromofenil)-4-(3-piperidinometil)-tieno [2,3-d] piridazinil-7- formamida;

2-(4-fluorofenil)-4-(3-tetra-hidropiranometil)-tieno[2,3-d]piridazinil-7- formamida;

2-(4-clorofenil)-4-(3-tetra-hidropiranometil)-tieno[2,3-d]piridazinil-7- formamida;

2-(4-bromofenil)-4-(3-tetra-hidropiranometil)-tieno[2,3-d]piridazinil-7- formamida;

2-(4-fluorofenil)-4-(3-tetra-hidrotiopiranometil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-clorofenil)-4-(3-tetra-hidrotiopiranometil)-tieno[2,3-d]piridazinil-7- formamida;

2-(4-bromofenil)-4-(3-tetra-hidrotiopiranometil)-tieno[2,3-d]piridazinil-7- formamida;

2-(4-clorofenil)-4-(2-piperidinometil)-tieno[2,3-d] piridazinil-7-formamida;

2-(4-clorofenil)-4-(4-piperidinometil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-clorofenil)-4-(S-3-piperidinometil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-clorofenil)-4-(R-3-piperidinometil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-clorofenil)-4-(3-piperidinometil)-tieno[2,3-d] piridazinil-7-N-metil formamida;

2-(4-clorofenil)-4-(3-piperidinometil)-tieno[2,3-d] piridazinil-7-N,N-dimetil formamida;

2-(4-clorofenil)-4-(3-tetra-hidrotiopiranometil)-tieno[2,3-d]piridazinil-7-N-metil formamida;

2-(4-clorofenil)-4-(3-tetra-hidrotiopiranometil)-tieno[2,3-d]piridazinil-7-N,N- dimetil formamida;

2-(4-clorofenil)-4-(3-tetra-hidropiranometil)-tieno[2,3-d]piridazinil-7-N-metil formamida;

2-(4-clorofenil)-4-(3-tetra-hidropiranometil)-tieno[2,3-d]piridazinil-7-N,N-dimetil formamida;

2-(4-fluorofenil)-4-(3-pirrolidinometil)-tieno[2,3-d]piridazinil-7- formamida;

2-(4-clorofenil)-4-(3-pirrolidinometil)-tieno[2,3-d]piridazinil-7- formamida;

2-(4-bromofenil)-4-(3-pirrolidinometil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-fluorofenil)-4-(3-tetra-hidrofuranometil)-tieno[2,3-d]piridazinil-7- formamida;

2-(4-clorofenil)-4-(3-tetra-hidrofuranometil)-tieno[2,3-d]piridazinil-7- formamida;

2-(4-bromofenil)-4-(3-tetra-hidrofuranometil)-tieno[2,3-d]piridazinil-7- formamida;

2-(4-fluorofenil)-4-(3-tetra-hidrotiofenometil)-tieno[2,3-d]piridazinil-7- formamida;

2-(4-clorofenil)-4-(3-tetra-hidrotiofenometil)-tieno[2,3-d]piridazinil-7- formamida;

2-(4-bromofenil)-4-(3-tetra-hidrotiofenometil)-tieno[2,3-d]piridazinil-7- formamida;

2-(4-clorofenil)-4-(3-pirrolidinometil)-tieno[2,3-d]piridazinil-7- formamida;

2-(4-clorofenil)-4-(S-3-pirrolidinometil)-tieno[2,3-d]piridazinil-7- formamida;

2-(4-clorofenil)-4-(R-3-pirrolidinometil)-tieno[2,3-d]piridazinil-7- formamida;

2-(4-clorofenil)-4-(3-pirrolidinometil)-tieno[2,3-d]piridazinil-7-N-metil formamida;

2-(4-clorofenil)-4-(3-pirrolidinometil)-tieno[2,3-d]piridazinil-7-N,N-dimetil formamida;

2-(4-clorofenil)-4-(3-tetra-hidrotiofenometil)-tieno[2,3-d]piridazinil-7-N-metil formamida;

2-(4-clorofenil)-4-(3-tetra-hidrotiofenometil)-tieno[2,3-d]piridazinil-7-N,Ndimetil formamida;

2-(4-clorofenil)-4-(3-tetra-hidrofuranometil)-tieno[2,3-d]piridazinil-7-N-metil formamida;

2-(4-clorofenil)-4-(3-tetra-hidrofuranometil)-tieno[2,3-d]piridazinil-7-N,N-dimetil formamida;

[019] More preferably, the compounds of formula (I) are selected as follows from: 2-(4-fluorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7 -formamide;

2-(4-chlorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-bromophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-fluorophenyl)-4-(3-tetrahydropyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(3-tetrahydropyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-bromophenyl)-4-(3-tetrahydropyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-fluorophenyl)-4-(3-tetrahydrothiopyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(3-tetrahydrothiopyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-bromophenyl)-4-(3-tetrahydrothiopyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(2-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(4-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(S-3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(R-3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide;

2-(4-chlorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide;

2-(4-chlorophenyl)-4-(3-tetrahydrothiopyranomethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide;

2-(4-chlorophenyl)-4-(3-tetrahydrothiopyranomethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethylformamide;

2-(4-chlorophenyl)-4-(3-tetrahydropyranomethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide;

2-(4-chlorophenyl)-4-(3-tetrahydropyranomethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide;

2-(4-fluorophenyl)-4-(3-pyrrolidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(3-pyrrolidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-bromophenyl)-4-(3-pyrrolidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-fluorophenyl)-4-(3-tetrahydrofuranmethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(3-tetrahydrofuranmethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-bromophenyl)-4-(3-tetrahydrofuranmethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-fluorophenyl)-4-(3-tetrahydrothiophenomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(3-tetrahydrothiophenomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-bromophenyl)-4-(3-tetrahydrothiophenomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(3-pyrrolidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(S-3-pyrrolidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(R-3-pyrrolidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(3-pyrrolidinomethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide;

2-(4-chlorophenyl)-4-(3-pyrrolidinomethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide;

2-(4-chlorophenyl)-4-(3-tetrahydrothiophenomethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide;

2-(4-chlorophenyl)-4-(3-tetrahydrothiophenomethyl)-thieno[2,3-d]pyridazinyl-7-N,Ndimethylformamide;

2-(4-chlorophenyl)-4-(3-tetrahydrofuranmethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide;

2-(4-chlorophenyl)-4-(3-tetrahydrofuranmethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide;

[020] Preferably, R3 is pyridinyl, α-pyranyl, Y-pyranyl, α-thiopyranyl, y-thiopyranyl, pyrrolidinyl, furanyl or thienyl, and their optical isomers.

2-(4-clorofenil)-4-(3-piridinometil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-bromofenil)-4-(3-piridinometil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-fluorofenil)-4-(3-α-piranometil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-clorofenil)-4-(3-α-piranometil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-bromofenil)-4-(3-α-piranometil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-fluorofenil)-4-(3-α-tiopiranometil)-tieno[2,3-d]piridazinil-7- formamida;

2-(4-clorofenil)-4-(3-α-tiopiranometil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-bromofenil)-4-(3-α-tiopiranometil)-tieno[2,3-d] piridazinil-7-formamida;

2-(4-clorofenil)-4-(2-piridinometil)-tieno[2,3-d] piridazinil-7-formamida;

2-(4-clorofenil)-4-(4-piridinometil)-tieno[2,3-d] piridazinil-7-formamida;

2-(4-clorofenil)-4-(3-piridinometil)-tieno[2,3-d]piridazinil-7-N-metil formamida;

2-(4-clorofenil)-4-(3-piridinometil)-tieno[2,3-d]piridazinil-7-N,N-dimetil formamida;

2-(4-clorofenil)-4-(3-tiopiranometil)-tieno[2,3-d]piridazinil-7-N-metil formamida;

2-(4-clorofenil)-4-(3-tiopiranometil)-tieno[2,3-d]piridazinil-7-N,N-dimetil formamida;

2-(4-clorofenil)-4-(3-piranometil)-tieno[2,3-d] piridazinil-7-N-metil formamida;

2-(4-clorofenil)-4-(3-piranometil)-tieno[2,3-d] piridazinil-7-N,N-dimetil formamida;

2-(4-fluorofenil)-4-(3-pirrolemetil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-clorofenil)-4-(3-pirrolemetil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-bromofenil)-4-(3-pirrolemetil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-fluorofenil)-4-(3-furanometil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-clorofenil)-4-(3-furanometil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-bromofenil)-4-(3-furanometil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-fluorofenil)-4-(3-tiofenometil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-clorofenil)-4-(3-tiofenometil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-bromofenil)-4-(3-tiofenometil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-clorofenil)-4-(2-pirrolemetil)-tieno[2,3-d] piridazinil-7- formamida;

2-(4-clorofenil)-4-(3-pirrolemetil)-tieno[2,3-d] piridazinil-7-N-metil formamida;

2-(4-clorofenil)-4-(3-pirrolemetil)-tieno[2,3-d]piridazinil-7-N,N-dimetil formamida;

2-(4-clorofenil)-4-(3-tiofenometil)-tieno[2,3-d]piridazinil-7-N-metil formamida;

2-(4-clorofenil)-4-(3-tiofenometil)-tieno[2,3-d]piridazinil-7-N,N-dimetil formamida;

2-(4-clorofenil)-4-(3-furanometil)-tieno[2,3-d] piridazinil-7-N-metil formamida;

2-(4-clorofenil)-4-(3-furanometil)-tieno[2,3-d] piridazinil-7-N,N-dimetil formamida;

2-(3,5-diclorofenil)-4-(3-piperidinometil)-tieno[2,3-d] piridazinil-7- formamida;

[021] More preferably, compounds of formula (I) are selected as follows from: 2-(4-fluorophenyl)-4-(3-pyridinomethyl)-thieno[2,3-d]pyridazinyl-7 - formamide;

2-(4-chlorophenyl)-4-(3-pyridinemethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-bromophenyl)-4-(3-pyridinemethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-fluorophenyl)-4-(3-α-pyranomethyl)-thieno[2,3-d] pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(3-α-pyranomethyl)-thieno[2,3-d] pyridazinyl-7-formamide;

2-(4-bromophenyl)-4-(3-α-pyranomethyl)-thieno[2,3-d] pyridazinyl-7-formamide;

2-(4-fluorophenyl)-4-(3-α-thiopyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(3-α-thiopyranomethyl)-thieno[2,3-d] pyridazinyl-7-formamide;

2-(4-bromophenyl)-4-(3-α-thiopyranomethyl)-thieno[2,3-d] pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(2-pyridinemethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(4-pyridinemethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(3-pyridinemethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide;

2-(4-chlorophenyl)-4-(3-pyridinemethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide;

2-(4-chlorophenyl)-4-(3-thiopyranomethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide;

2-(4-chlorophenyl)-4-(3-thiopyranomethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide;

2-(4-chlorophenyl)-4-(3-pyranomethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide;

2-(4-chlorophenyl)-4-(3-pyranomethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide;

2-(4-fluorophenyl)-4-(3-pyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(3-pyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-bromophenyl)-4-(3-pyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-fluorophenyl)-4-(3-furanomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(3-furanomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-bromophenyl)-4-(3-furanomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-fluorophenyl)-4-(3-thiophenomethyl)-thieno[2,3-d] pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(3-thiophenomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-bromophenyl)-4-(3-thiophenomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(2-pyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

2-(4-chlorophenyl)-4-(3-pyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide;

2-(4-chlorophenyl)-4-(3-pyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide;

2-(4-chlorophenyl)-4-(3-thiophenomethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide;

2-(4-chlorophenyl)-4-(3-thiophenomethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide;

2-(4-chlorophenyl)-4-(3-furanomethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide;

2-(4-chlorophenyl)-4-(3-furanomethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide;

2-(3,5-dichlorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide;

[022] According to another aspect of the present invention, a pharmaceutical composition is provided, including compounds of formula (I) having a therapeutically effective amount and their pharmaceutically acceptable salts or hydrates, and pharmaceutically acceptable carriers.

[023] The pharmaceutical compositions of the present invention can be administered locally, such as in the lung, head, colon and so on, in the form of solution, suspension, aerosol or dry powder and so on; or systematically by oral administration in the form of tablets, powder, or administered parenterally, in the form of a solution or suspension, or subcutaneous administration, or rectal administration in the form of a suppository, or percutaneous administration.

[024] According to another aspect of the present invention, uses of the compounds of formula (I) or pharmaceutically acceptable salts or hydrates thereof in the preparation for medicaments for the treatment or prophylaxis of tumor diseases are provided. Where said tumor diseases include cervical tumor, head and neck tumor, breast, ovarian, lung (non-small cell) carcinoma, pancreas, colon, prostate or other tissues, as well as leukemias and lymphomas, central nervous system tumors and peripheral and other tumors such as melanoma, fibrosarcoma and osteosarcoma.

[025] According to a further aspect of the present invention, uses of the compounds of formula (I) or pharmaceutically acceptable salts or hydrates thereof in the preparation for medicaments for the treatment or prophylaxis of proliferative diseases are provided. Where said proliferative diseases include autoimmune, inflammatory, neurological and cardiovascular diseases.

[026] According to one aspect of the present invention, uses of the compounds of formula (I) or pharmaceutically acceptable salts or hydrates thereof in the preparation for drugs limiting cell proliferation in humans or animals are provided.

[027] Yet, according to another aspect of the present invention, uses of the compounds of formula (I) or pharmaceutically acceptable salts or hydrates thereof in the preparation for tumor inhibitory drugs or kinases associated with growth factors are provided.

[028] For the above mentioned uses, the dosage depends on the compounds used, administration approaches, and the treatments required by the diseases.

[029] According to the last aspect of the present invention, the methods of the compounds of formula (I) or pharmaceutically acceptable salts or hydrates thereof are provided, and the method includes the following steps:

depois, é tratado com hidrazina para produzir o composto de fórmula B:

o composto de fórmula B é tratado com oxicloreto de fósforo para produzir o composto de fórmula C:

e o composto de fórmula C reage com o composto R3CH2, para produziro composto de fórmula D,

e depois, o composto de fórmula D reage com NHR1R2, o grupo protetor em R3 é, então, removido e tratado com um álcali para produzir os compostos de fórmula (I) ou sais farmaceuticamente aceitáveis ou seus hidratos a partir deles,

onde R é um alcalino C1-4, e R1 e R2 são independentemente H ou alcalino C1-4 respectivamente; R3 é um anel de 6 ou 5 membros saturado ou insaturado contendo N, S ou O, e seus isômeros óticos; R4 é uma halofenila monossubstituída or dissubstituída em qualquer posição.[030] In the presence of alkali, the compound of formula A is treated with dialkyl oxalates:

then, it is treated with hydrazine to produce the compound of formula B:

the compound of formula B is treated with phosphorus oxychloride to produce the compound of formula C:

and the compound of formula C reacts with the compound R3CH2 to produce the compound of formula D,

and then, the compound of formula D reacts with NHR1R2, the protecting group on R3 is then removed and treated with an alkali to produce the compounds of formula (I) or pharmaceutically acceptable salts or hydrates thereof therefrom,

where R is a C1-4 alkali, and R1 and R2 are independently H or C1-4 alkali respectively; R3 is a 6- or 5-membered saturated or unsaturated ring containing N, S or O, and their optical isomers; R4 is a halophenyl monosubstituted or disubstituted at any position.

Toluene = Tolueno sealed tube = tubo selado O processo de síntese do 2-(4-clorofenil)-4-(3-piperidinometil)-tieno[2,3-d] piridazinil -7- formamida.[031] The synthesis process of the present invention is described below:

Toluene = Toluene sealed tube = sealed tube The synthesis process for 2-(4-chlorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide.

[032] Where the compound of formula A can be prepared by conventional chemical processes in the field, or be commercially sold. After being obtained, the compound of formula A is condensed with dialkali oxalates, for example, diethyl oxalate, in the presence of alkali such as common alkali LDA (lithium diisopropylamide) and common organic solvents such as tetrahydrofuran to produce compound Y. The condensation reaction must be carried out at a low temperature due to the presence of LDA. It is easy for people skilled in the art to obtain LDA that is usually freshly brewed at a low temperature.

[033] Then, compound Y reacts with hydrazine such as H2NNH2 in alcoholic solvent to produce the compound of formula B.

[034] The compound of formula B is treated with phosphorus oxychloride for an acylation reaction to produce the compound of formula C.

[035] The three steps above refer to a method of synthesis of the intermediate product of the thienopyridazine compound produced by F. Hoffman-La Roche AG in WO2005105808.

[036]R3CH2 compounds with a Boc protecting group are prepared by conventional methods in the field and heated to a reaction temperature of 80~90°C in the presence of catalysts such as PdCl2 (dppf) and solvents such as phosphates / 1 ,4-dioxane, the compound of formula C reacts with R3CH2 containing a Boc protecting group to overnight to produce the compound of formula D. In the above reactions, the compounds of R3CH2 must be pretreated with 9-BBN, please consult the “Suzuki-Miyaura” coupling reaction, p6125-6128, Tetrahedron Letters 45 (2004).

[037] The compounds of formula D and HNR1R2 are amonolyzed in a sealed container using conventional methods with the reaction solvents of 1,4-dioxane, under heating at a temperature of 80°C overnight, then the protective group Boc in R3 is removed under acidic conditions to obtain the acid salts of formula (I), and adjust the pH with alkaline to produce the compounds of formula (I).

[038] The raw materials of the aforementioned preparations are obtained by commercial suppliers or are prepared by conventional methods in the field.

DETAILED DESCRIPTION OF THE INVENTION

[039] In the following, the present invention will be specifically described with reference to the examples. The examples are given for illustration only of the technical solution of the present invention and are not to be interpreted to limit the present invention.

[040] Where the structure of the components of formula (I) is determined by nuclear magnetic resonance (NMR) and mass spectrometric techniques; chemical changes by proton NMR are measured using δ scale, and peak multiplicity is represented as follows: s, single peak; m, multiple peak. The intermediate product is usually represented by mass and NMR spectrometry.

Example 1: 2-(4-chlorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide Step 1: Synthesis of 5-Bromo-thiophene-3-formic acid

[041]

[042] Thiophene-3-formic acid (12.6g) and AcOH (96ml) are added to a reaction flask (250ml), to dissolve after stirring at room temperature, HBr solution (8ml) is added to a flask of reaction and the reaction quickly changes to a pale yellow. Pyridinium bromide perpromide (27g) is then added to the vial gradually at room temperature. After addition, the reaction is further stirred at room temperature, and monitored by HPLC. The above mixture is poured into ice water after the reaction, stirred for approximately 30 minutes, filtered to form a white powder solid, the white powder solid is crystallized with hot water, filtered and dried to obtain a 5-bromo acid crystal. - thiophene-3-formic (10.8g), 92% content measured by HPLC.

[043] Thiophene-3-formic acid (12.5g), AcOH (83ml) are added to a reaction flask (500ml), stirred at room temperature and dissolved to obtain a colorless liquid. A solution of Br2 (5.4ml) in AcOH (100ml) is placed in a constant pressure funnel and dropped into the reaction flask at room temperature and kept at a temperature below 25°C. After addition, the reaction is carried out at room temperature overnight. The reaction mixture is poured into ice water the next day, stirred for about 30 minutes, filtered to form a white powdery solid. The white powder solid is crystallized with hot water, filtered and dried to obtain a white crystal of 5-bromo-thiophene-3-formic acid (10g), content of 92% measured by HPLC.

Step 2: Synthesis of 5-bromo-thiophene-3-ethyl

[044]

[045] 5-Bromo-thiophene-3-formic acid (18.5g) obtained by the above step, absolute ethanol (150 ml) and concentrated sulfuric acid (5 ml) are added in a three-neck flask (500 ml) and heated under reflux, and vaporized under reduced pressure to remove the solvent after the reaction. Then, ethyl acetate (100ml) and saturated water (200ml) are added and stirred for layer separation. The aqueous layer is re-extracted with ethyl acetate (25ml*2) twice. The organic phase is combined and transferred to a separatory funnel. Sodium carbonate solution (10%) is added to a separatory funnel to adjust pH=8 and then separated, and an organic phase is washed with saturated brine to pH=7, and dried with anhydrous magnesium sulfate throughout. overnight, and filtered the next day, and sprayed under reduced pressure to remove the solvent to obtain a pale yellow oily liquid of 5-bromo-thiophene-3-ethyl formate (15g).

Step 3: Synthesis of 4-chlorophenylboric acid

[046]

[047]4-Bromochlorobenzene (70.6g) is added to a four-neck flask connecting with a mechanical stirring apparatus, two constant pressure funnels and a temperature probe. Toluene (588.3ml) and tetrahydrofuran (THF) (147ml) are added under stirring at room temperature under argon, and dissolved to obtain a colorless liquid. Then triisopropyl borate (109.2ml) and n-butyl lithium (176.4ml, 2.5M in hexane) are respectively added in two constant pressure funnels, and the internal temperature cooled to below -78°C, then the n-butyl lithium solution is dripped into a flask under drip rate control to keep the internal temperature below -78°C. After addition, the mixture is kept at temperature for 1 hour, then triisopropyl borate is dropped into the mixture at a temperature below -78°C, and kept at temperature for 1 hour after addition and then the cooling system is removed to naturally warm to -20°C. HCl solution (360.4ml, 2.2M) is added to warm to about 10°C and then placed for layer separation. The aqueous phase is re-extracted with toluene (58.8ml, 2 times). The organic phase is combined together and washed with saturated brine until pH=7 to obtain a clear liquid, dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove most of the solvents and the white solid is finally precipitated, filtered. to obtain a crystal of 4-chlorophenylboric acid (48g).

Step 4: Synthesis of 5-(4-chlorophenyl)-thiophene-3-ethyl

[048]

[049] 5-(4-Chlorophenyl)-thiophene 3-ethyl formate (10.5g), 4-chloro-phenylboronic acid (6g), Pd[P(Ph)3]4 (1.5g), carbonate sodium (7.5g) and a solvent mixture of toluene:water:EtOH (4:2:1, v/v) are, one after the other, added to a three-neck flask (500ml) and heated under reflux for 3 hours, the reaction is tracked by TLC. The reaction mixture is cooled to room temperature after the reaction and placed for layer separation. The aqueous phase is re-extracted with toluene (35ml, 2 times). The organic phase is combined together and washed with saturated brine to pH=7, dried with anhydrous sodium sulfate overnight and filtered the next day, and then evaporated under reduced pressure to remove solvents to obtain a viscous yellow fluid. clear, and placed to obtain a coagulated solid, and recrystallized from absolute EtOH to obtain a crystal of 5-(4-chlorophenyl)-thiophene-3-ethyl formate (8.6g). 1HNMR(500MHz, DMSO ), δ 8.30(sc, 1H), 7.81(s, 1H), 7.72(m, 2H), 7.46(m, 2H), 4.27(m, 2H), 1.30(m, 3H).

Step 5: Synthesis of 5-(4-chlorophenyl)-2-ethoxyoxalyl-thiophene-3-ethyl

[050]

[051] Preparation of LDA: THF (252.6ml) and N,N-diisopropylamine (79ml) are added in a 3-neck flask (1000ml) under argon, and n-butyl lithium (302.8ml, 1.6M) in hexane) is placed in a constant pressure funnel (500ml) and dropped into the flask when the internal temperature is below -20˚C with an intensely exothermic reaction, and maintained at -20˚C～-30˚C of the internal temperature by controlling a speed of addition; after addition, the above mixture is naturally warmed to room temperature and directly used for the following condensation reaction.

[052] Condensation reaction: 5-(4-chlorophenyl)-3-thiophene-ethyl formate (28.7g), THF (1084ml) and diethyl oxalate (29.7ml) are added in a four-necked flask (2000ml ) connecting with the mechanical stirring apparatus, two constant pressure funnels and a temperature probe. The mixture is stirred at room temperature and dissolved to obtain a clear, pale yellow liquid. The LDA solution prepared by the above step is transferred to a constant pressure funnel and cooled to a temperature below -78°C and the LDA is dripped to evaporation under argon at a temperature below -78°C controlling the speed of drip, after addition, the reaction is tracked by TLC. HCl solution (2.2M) is added until evaporation after the reaction, and adjusted to pH~3, and the color of the reaction liquid is changed from reddish-brown to orange. The temperature is warmed to approximately 0°C, a solid NaCl is then added and stirred until dissolved, and placed for layer separation. The aqueous phase is re-extracted with THF (143.5ml, 2 times). The organic phase is combined and washed with saturated brine twice and then adjusted to pH=8 with dilute sodium carbonate solution; finally washed with saturated brine to pH=7, dried with anhydrous sodium sulphate, filtered and evaporated under reduced pressure to remove solvent to obtain a pale yellow viscous fluid and placed at room temperature until it gradually becomes a solid , and recrystallized from EtOH to obtain a pure product of 5-(4-chlorophenyl)-2-ethoxyoxalyl-thiophene-3-ethyl formate (orange crystal, 25.5g). 1HNMR (500MHz, CD3Cl), δ 7.61(s, 1H), 7.59(m, 2H), 7.42(m, 2H), 4.37(m, 4H), 1.39(m, 6H).

Step 6: Synthesis of 2-(4-chlorophenyl)-4-oxo-4,5-dihydro-thiero[2,3-d]pyridazinyl-7-ethyl

[053]

[054] A 5-(4-chlorophenyl)-2-ethoxyoxalyl-thiophene-3-ethyl formate crystal (3.0g), absolute ethanol (45ml) are added to a reaction flask (100ml), stirred at the temperature environment to obtain a yellow suspension. Hydrazine hydrate (0.75ml) is added to a constant pressure funnel, shaken for 10 minutes and then dropped into the reaction vessel. The yellow suspension is dissolved until a clear liquid is reached and the above mixture is heated to 70°C and a yellow solid in the flask is gradually precipitated with increasing temperature and the reaction liquid becomes increasingly viscous. The reaction mixture is kept for 1h and then cooled to room temperature, filtered to obtain a pistachio green solid, and this solid is washed with a mixture of hexane/dichloromethane (1:1) (15ml, 2 times) and methanol/dichloromethane (1:1) (15ml, 2 times) and dried under reduced pressure to obtain 2-(4-chlorophenyl)-4-oxo-4,5-dihydro-thieno formate [2,3-d ]pyridazinyl-7-ethyl (2.75g).

Step 7: Synthesis of 4-chloro-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl

Formato de 2-(4-clorofenil)-4-oxo-4,5-dihidro-tiero[2,3-d]piridazinil-7-etila (1,5g), oxicloreto de fósforo (22,5ml) são adicionados a um frasco de três bocas (100ml), aquecidos a 95°C por 3 h, e dissolvidos até obter uma solução marrom-vermelho- escuro. Após a reação, a solução é resfriada até a temperatura ambiente e evaporada sob pressões reduzidas para remover o solvente e obter um fluido viscoso marrom-chocolate. Tetra-hidrofurano e água salgada saturada são adicionados ao fluido e agitados, e um sólidos amarelos é precipitado, depois a solução é filtrada, colocada para separação de camadas e reextraída; ajustada até pH=9 com uma solução de carbonato de sódio após a fase orgânica ser combinada; finalmente lavada com água salgada saturada até pH=7, e seca com sulfato de sódio anidro, filtrada, descolorida com carvão ativado em refluxo para obter um líquido verde- amarelo-claro; e o fluido é evaporado sob pressão reduzida até remover o solvente para obter formato de 4-cloro-2-(4-clorofenil)-tieno[2,3-d]piridazinil -7-etila (sólido floculento verde-claro,1,0g). 1HNMR(500MHz, CD3C1 ), δ 7,74 (m, 3H), 7,59(m, 2H), 4,65(m, 2H), 1,55(m, 3H). HRMS（ MS alta resolução） MW＝351,98. Etapa 8: Síntese de N-Boc-3-metileno piperidina[055]

2-(4-Chlorophenyl)-4-oxo-4,5-dihydro-thiero[2,3-d]pyridazinyl-7-ethyl formate (1.5g), phosphorus oxychloride (22.5ml) are added to a three-neck flask (100ml), heated to 95°C for 3 h, and dissolved to a dark red-brown solution. After the reaction, the solution is cooled to room temperature and evaporated under reduced pressure to remove the solvent and obtain a viscous chocolate-brown fluid. Tetrahydrofuran and saturated brine are added to the fluid and stirred, and a yellow solid is precipitated, then the solution is filtered, placed for layer separation and re-extracted; adjusted to pH=9 with a sodium carbonate solution after the organic phase is combined; finally washed with saturated brine until pH=7, and dried with anhydrous sodium sulfate, filtered, decolorized with activated charcoal at reflux to obtain a pale yellow-green liquid; and the fluid is evaporated under reduced pressure to remove the solvent to obtain 4-chloro-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl formate (light green flocculent solid,1, 0g). 1HNMR(500MHz, CD3Cl), δ 7.74(m, 3H), 7.59(m, 2H), 4.65(m, 2H), 1.55(m, 3H). HRMS（ MS high resolution） MW＝351.98. Step 8: Synthesis of N-Boc-3-methylene piperidine

[056]

[057] Triphenylmethyl phosphonium iodide (22.14g) and toluene (135ml) are added to a three-neck flask (500ml), stirred at room temperature until a milky white suspension is obtained and quickly changed to orange after potassium tert-butanolate (5.31g) be added. Then, N-Boc-3-piperidone (6.0g) in toluene (66ml) is added to a constant pressure funnel and dropped into a flask under argon in the case of an exothermic phenomenon, and kept at a temperature of 30° C and the reaction is tracked by TLC after addition. After the reaction, the mixture is filtered and washed with saturated brine (200ml, 2 times) and then adjusted to pH~3 with dilute HCl (1M), and then washed with saturated brine to pH=7, dried with sulfate anhydrous sodium and filtered to obtain a clear yellow liquid. The clear yellow liquid is purified along with silica gel by chromatography (elution liquid: petroleum ether:ethyl acetate =15:1) to obtain a yellow oily liquid of N-Boc-3-methylene piperidine (4.2g). 1HNMR(400MHz, CD3Cl), δ 4.83(s, 1H), 4.76(s, 1H), 3.89(s, 2H), 3.45(m, 2H), 2.26(m, 2H) 1.64(s, 2H), 1.51(s, 9H).

Step 9: Synthesis of 4-(1-Boc-3-piperidinomethyl)-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl

[058]

[059] N-Boc-3-methylene pyrazidine (0.4g) is added to a three-neck flask under argon and cooled to 0°C. 9-BBN solution (12ml, 0.5M in THF) is injected into the reaction vial with a syringe and held for 30 minutes, then warmed to room temperature for 2 hours, and evaporated to remove solvent under reduced pressure (25°C). 1,4-dioxane (20ml), PdCl2 (dppf) (0.05g), potassium phosphate (0.32g) and 4-chloro-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl formate -7- ethyl are added to the reaction flask and heated at 90°C overnight. The reaction mixture is cooled to room temperature the next day, then ice water (50ml) and ethyl acetate (50ml) are added, stirred for approximately 15 minutes and placed for layer separation. The water layer is re-extracted with ethyl acetate 3 times, the organic phase is combined and washed with saturated brine until pH=7, dried with anhydrous magnesium sulfate and filtered. The filtered liquid is purified with silica gel by chromatography (ethyl acetate: petroleum ether = 1:5) to obtain an orange viscous fluid (0.6g), and ethanol (2ml) is added to the fluid and crystallized in the refrigerator to obtain a solid of 4-(1-Boc-3-piperidinomethyl)-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl formate (0.3g). 1HNMR(400MHz, DMSO ), δ 8.90(s, 1H), 8.03(m, 2H), 7.63(m, 2H), 4.54(m, 2H), 3.73(s, 2H), 3.32(m, 2H), 3.28(m, 1H), 2.82(m, 2H), 2.09(s, 1H), 1.78(s, 1H), 1, 64(s, 1H), 1.44(m, 3H), 1.39(s, 1H), 1.32(s, 9H). MS (EI): 515 (M+), 486, 458, 442, 414, 334, 332, 306, 304, 149, 57.

Step 10: Synthesis of 4-(1-Boc-3-piperidinomethyl)-2(4-chlorophenyl)-7-aminocarbonyl-thieno[2,3-d]pyridazine

[060]

[061] 4-(1-Boc-3-piperidinomethyl)-2-(4-chlorophenyl)-thieno[2,3-d]pyradazinyl-7-ethyl formate (0.3g), 1,4-dioxane ( 5ml) and NH3.H2O (5ml) are added to a sealed tube (25ml) and heated at 80°C overnight. The reaction mixture is cooled to room temperature and transferred to a separatory funnel the next day, ethylene acetate is also added, stirred, and then placed for layer separation. The water layer is re-extracted with ethyl acetate twice, the organic phase is combined together and adjusted to pH~3 with 1M HCl solution, and then washed with saturated brine until pH=7, dried with magnesium sulfate. anhydrous and filtered. The filtered liquid is purified with silica gel by chromatography (ethyl acetate:petroleum ether = 1:5) to obtain a solid of 4-(1-Boc-3-piperidinomethyl)-2(4-chlorophenyl)-7- aminocarbonyl-thieno[2,3-d]pyridazine (0.22g) 1HNMR(500MHz, CDCl3), δ 8.10(s, 1H), 7.77(m, 2H), 7.66(s, 1H) , 7.48(m, 2H), 5.90(s, 1H), 4.05(s, 1H), 3.88(m, 1H), 3.31(m, 1H), 3.21( m, 1H), 2.81(m, 2H), 2.28(s, 1H), 1.81(s, 1H), 1.67(s, 3H), 1.39(s, 9H). MS(ESI): 487(M+1),

Step 11: Synthesis of 2-(4-chlorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide hydrochloride

[062]

[063] 4-(1-Boc-3-piperidinomethyl)-2(4-chlorophenyl)-7-aminocarbonyl-thieno[2,3-d]pyridazine (200g) and ethyl acetate (4ml) are added to a flask of a mouth (25ml) and dissolved in a clear light yellow solution, HCl (4ml, 3M) is added and the solution quickly changes to a white suspension, heated at 30°C for 1h, and the suspension changes to clear and the reaction is tracked by plate; after reaction, the above mixture is evaporated under reduced pressure to remove the solvent and obtain a solid of 2-(4-chlorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-hydrochloride formamide (100 mg). 1HNMR(500MHz, DMSO), δ9.51(m, 1H), 9.09(m, 1H), 8.79(s, 1H), 8.66(s, 1H), 8.29(s, 1H) ), 8.08(m, 2H), 7.62(m, 2H), 3.45(m, 2H), 3.4(m, 1H), 3.17(m, 1H), 2.79 (m, 2H), 2.52(m, 1H), 1.81(m, 2H), 1.77(m, 1H), 1.42(m, 1H). MS(ESI):387(M+1).

Step 12: Synthesis of 2-(4-chlorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide

[064]

[065] 2-(4-Chlorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide hydrochloride (100 mg) is added to a one-mouth flask, then there is addition of water (5ml) and the sodium carbonate is dropped until pH=9~10, and stirred for 30min. The above mixture is extracted by ethyl acetate, washed with water, and evaporated under reduced pressure to remove the solvent and obtain 2-(4-chlorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl -7-formamide (70 mg).

Example 2 2-(4-chlorophenyl)-4-(3-tetrahydropyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide

[066]

Step 1:

[067] DMPU (225ml), FeCl3 (0.75g) and CuCl (0.3g) are added to 3-bromomethyltetrahydropyran (24.75g, 0.138mol) and then Et2Zn (106.8ml) is lightly dripped at 40~45°C for 45 minutes to obtain a zinc reagent.

[068] THF (810 m) and PdCl2(dppf) (5.09 g) are added to 4-chloro-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (30g) and then there is addition of zinc reagent in the THF solution to react at 45°C for 4 hours. The above mixture is poured into saturated water, filtered after stirring for 15 minutes and placed for layer separation. The aqueous phase is extracted with THF (500 ml twice). The organic phase is combined together, washed with saturated brine (500ml, 3 times), dried with anhydrous Na 2 SO 4 and evaporated under reduced pressure to remove the solvent and obtain 4-(3-tetrahydropyranomethyl)-2-(4-chlorophenyl) )-thieno[2,3-d]pyridazinyl-7-ethyl (25 g). MS (ESI): 417(M+1)

Step 2:

[069] 4-(3-Tetrahydropyranomethyl)-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl formate (3g), 1,4-dioxane (5ml) and NH3.H2O (5ml) is added to a sealed tube (25ml) and heated to 80°C overnight, cooled to room temperature overnight and transferred to a separatory funnel the next day, there is also addition of ethyl acetate, vibrated, the solution is then shaken, and placed for layer separation. The aqueous layer is re-extracted with ethyl acetate 2 times. The organic phase is combined and adjusted with 1M HCl solution to pH~3, then washed with saturated brine until pH=7, dried with anhydrous Na2SO4 and filtered. The filtered liquid is purified with silica gel by chromatography to obtain a solid of 2-(4-chlorophenyl)-4-(3-tetrahydropyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide (2 g) . MS (ESI): 388(M+1)

Example 3 2-(4-chlorophenyl)-4-(3-tetrahydrothiopyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide

[070]

Step 1:

[071]DMPU (225ml), FeCl3 (0.75 g) and CuCl (0.3 g) are added to 3-bromomethyl tetrahydrothiopyran (24.75g, 0.138mol) and then Et2Zn (106.8ml) it is slowly added at 40~45°C for 45 minutes to obtain a zinc reagent.

[072] THF (810 ml) and PdCl2(dppf) (5.09 g) are added to 4-chloro-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (30g) and then the zinc reagent is dropped into the THF solution at 45°C for 4 hours. The reaction mixture is poured into saturated brine, filtered, after stirring for 15 minutes, and placed for layer separation. The aqueous phase is extracted with THF (500 ml, 2 times). The organic phase is combined, washed with saturated brine (500ml, 3 times), dried over anhydrous Na2SO4 and evaporated under reduced pressure to remove the solvent and obtain 4-(3-tetrahydropyranomethyl)-2-(4-chlorophenyl) )-thieno[2,3-d]pyridazinyl-7-ethyl (25 g). MS (ESI): 433(M+1)

Step 2:

[073] 4-(3-Tetrahydropyranomethyl)-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl formate (3g), 1,4-dioxane (5 ml) and NH3.H2O (5 ml) is added to a sealed tube (25 ml) and heated to 80°C overnight, then cooled to room temperature and transferred to a separatory funnel the next day, and acetate is also added. of ethyl, shaking, to finally be placed for layer separation. The aqueous layer is re-extracted with ethyl acetate 2 times. The organic phase is combined together and adjusted with 1M HCl solution to pH~3, then washed with saturated brine to pH=7, dried with anhydrous Na2SO4 and filtered. The filtered liquid is purified with silica gel by chromatography to obtain a solid of 2-(4-chlorophenyl)-4-(3-tetrahydropyranomethyl)-thienod]pyridazinyl-7-formamide (2 g). MS (ESI): 404(M+1)

Example 4 2-(4-chlorophenyl)-4-(2-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide

[074]

Step 1:

[075] DMPU (225ml), FeCl3 (0.75 g) and CuCl (0.3 g) are added to N-Boc-2-bromomethyl piperidine (24.75g, 0.138mol) and then Et2Zn (106, 8ml) is slowly added at 40~45˚C for 45 minutes to obtain a zinc reagent.

[076] THF (810 ml) and PdCl2(dppf) (5.09 g) are added to 4-chloro-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (30g) and then the zinc reagent is added to the THF solution at 45°C for 4 hours. The reaction mixture is poured into saturated brine, filtered after stirring for 15 minutes and placed for layer separation. The aqueous phase is extracted with THF (500 ml, 2 times). The organic phase is combined, washed with saturated water (500ml, 3 times) and dried over anhydrous Na2SO4 and evaporated under reduced pressure to remove the solvent and obtain 2-(4-chlorophenyl)-4-(N-Boc-2 formate - piperidinomethyl) - thieno[2,3-d] pyridazinyl-7-ethyl (25 g). MS (ESI): 516(M+1)

Step 2:

[077] 2-(4-Chlorophenyl)-4-(N-Boc-2-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-ethyl (3g), 1,4-dioxane (5ml) and NH3.H2O (5ml) is added to a sealed tube (25ml) and heated to 80°C overnight. The reaction mixture is cooled to room temperature and transferred to a separatory funnel the next day, ethyl acetate is also added, stirring, to finally be placed for layer separation. The water layer is re-extracted with ethyl acetate 2 times, the organic phase is combined and adjusted to pH~3 with 1M HCl solution and then washed with brine until pH=7, dried with anhydrous Na2SO4 and filtered. The filtered liquid is purified with silica gel by chromatography to obtain a solid of 2-(4-chlorophenyl)-4-(N-Boc-2-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide (2g) . MS (ESI): 487(M+1)

Step 3:

[078] 4-(N-Boc-2-piperidinomethyl)-2(4-chlorophenyl)-7-aminocarbonyl-thieno[2,3-d]pyridazine (200mg) and ethyl acetate (4ml) are added to a flask of one mouth (25ml) and dissolved until one reaches a clear pale yellow solution. HCl solution (4ml, 3M) is added and a white suspension is obtained, this is heated to 30°C for 1h and the white suspension is changed to clear. The reaction is tracked by plate. After the reaction, the solvent is evaporated under reduced pressure until removing the solvent and obtaining a solid of 2-(4-chlorophenyl)-4-(N-Boc-2-piperidinomethyl)-thieno[2,3-d] hydrochloride pyridazinyl-7-formamide (100 mg). MS (ESI): 423(M+1)

Step 4:

[079] 2-(4-Chlorophenyl)-4-(N-Boc-2-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide hydrochloride (100 mg) is added to a one-neck flask , after adding water (5ml) and the sodium carbonate is dropped until pH=9~10, the solution is stirred for 30min. The above mixture is extracted by ethyl acetate, washed and evaporated under reduced pressure until removing the solvent and obtaining 2-(4-chlorophenyl)-4-(2-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7- formamide (70 mg). MS (ESI): 387(M+1)

Example 5 2-(4-chlorophenyl)-4-(4-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide

Etapa 1:[080]

Step 1:

[081] DMPU (225ml), FeCl3 (0.75g) and CuCl (0.3g) are added to N-Boc-4-bromomethylpiperidine (24.75g, 0.138mol) and then Et2Zn (106.8ml) is slowly dripped at 40~45°C for 45 minutes to obtain a zinc reagent.

[082] THF (810 ml) and PdCl2(dppf) (5.09 g) are added to 4-chloro-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl formate ( 30g) and then the zinc reagent is dropped into the THF solution at 45°C for 4 hours. The reaction mixture is poured into saturated brine, filtered after stirring for 15 minutes and placed for layer separation. The aqueous phase is extracted with THF (500 ml, 2 times). The organic phase is combined, washed with saturated brine (500 ml, 3 times) and dried with Na2SO4, evaporated under reduced pressure to remove solvent and obtain 2-(4-chlorophenyl)-4-(N-Boc-4- piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-ethyl (25 g). MS (ESI): 515(M+1)

Step 2:

[083] 2-(4-chlorophenyl)-4-(N-Boc-4-piperidinomethyl)-thieno[2,3-d] pyridazinyl-7-ethyl (3g), 1,4-dioxane (5ml) and NH3 .H2O (5ml) are added to a sealed tube (25ml) and heated to 80°C overnight. The reaction mixture is cooled to room temperature in a separatory funnel the next day, and ethyl acetate is added, stirring, and finally placed for layer separation. The water layer is re-extracted with ethyl acetate 2 times, the organic phase is combined and adjusted to pH~3 with 1M HCl solution, then washed with brine until pH=7, dried with anhydrous Na2SO4 and filtered. The filtered liquid is purified with silica gel by chromatography to obtain a solid of 2-(4-chlorophenyl)-4-(N-Boc-4-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide (2g) . MS (ESI): 487(M+1)

Step 3:

[084] 4-(N-Boc-4-piperidinomethyl)-2-(4-chlorophenyl)-7-aminocarbonyl-thieno[2,3-d]pyridazine (200mg) and ethyl acetate (4ml) are added to one one-mouth vial (25ml) and dissolved to a clear pale yellow solution. HCl solution (4ml, 3M) is added and changed to a white suspension, heated to 30°C for 1 h and the white suspension changed to clear. The reaction is tracked by plate. After the reaction, the mixture is evaporated under reduced pressure to remove the solvent and obtain a solid of 2-(4-chlorophenyl)-4-(4-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-hydrochloride formamide (100 mg). MS (ESI): 423(M+1)

Step 4:

[085] 2-(4-Chlorophenyl)-4-(4-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide hydrochloride is added to a one-mouth flask (25ml), then water (5ml) ) is added and the sodium carbonate is dropped until pH=9~10 stirred for 30min. The above mixture is extracted by ethyl acetate, washed and evaporated under reduced pressure to remove solvent and obtain 2-(4-chlorophenyl)-4-(4-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide (70mg). MS (ESI): 387(M+1)

Example 6: 2-(4-chlorophenyl)-4-(3-pyrrolidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide

Etapa 1:[086]

Step 1:

[087] DMPU (225ml), FeCl3 (0.75 g) and CuCl (0.3 g) are added to N-Boc-3-bromomethylpyrrole (24.75g, 0.138mol) and then Et2Zn (106.8ml) ) is slowly dropped at 40~45°C for 45 minutes to obtain a zinc reagent.

[088] THF (810ml) and PdCl2 (dppf) (5.09g) are added to 4-chloro-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (30g) and, then the zinc reagent is added to the THF solution at 45°C for 4h. The reaction mixture is poured into saturated brine, filtered after stirring for 15 minutes and placed for layer separation. The aqueous phase is extracted with THF (500 ml, 2 times). The organic phase is combined, washed with saturated brine (500ml, 3 times), dried with anhydrous Na2SO4, and finally evaporated under reduced pressure to remove the solvent and obtain 2-(4-chlorophenyl)-4-(N -Boc-3-tetrahydropyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-ethyl (25g). MS (ESI): 502(M+1)

Step 2:

[089] 2-(4-Chlorophenyl)-4-(N-Boc-3-tetrahydropyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-ethyl formate (3g), 1,4-dioxane ( 5ml) and NH3.H2O (5ml) are added to a sealed tube (25ml) and heated at 80°C overnight. The reaction liquid is cooled to room temperature and transferred to a separating funnel the next day, and ethyl acetate is added, shaken, placed for layer separation. The water layer is re-extracted with ethyl acetate 2 times, the organic phase is combined together and adjusted to pH~3 with 1M HCl solution and then washed with saturated brine until pH=7, dried with anhydrous Na2SO4 and filtered. The filtered liquid is purified with silica gel by chromatography to obtain a solid of 2-(4-chlorophenyl)-4-(N-Boc -3-tetrahydropyrrole methyl)-thieno[2,3-d]pyridazinyl-7- formamide (2g). MS (ESI): 473(M+1)

Step 3:

[090] 4-(N-Boc-3-tetrahydropyrrolemethyl)-2(4-chlorophenyl)-7-aminocarbonyl-thieno[2,3-d]pyridazine (200mg) and ethyl acetate (4ml) are added to a one-mouth vial (25ml) and dissolved into a clear, pale yellow solution. HCl solution (4ml, 3M) is added and changed to a white suspension, heated at 30°C for 1 h until clear. The reaction is tracked by plate. After the reaction, the solution is evaporated under reduced pressure to remove solvent to obtain a solid of 2-(4-chlorophenyl)-4-(3-tetrahydropyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-hydrochloride. -formamide (100 mg). MS (ESI): 409(M+1)

Step 4:

[091] 2-(4-Chlorophenyl)-4-(3-tetrahydropyrrolemethyl)-thieno[2,3-d] pyridazinyl-7-formamide hydrochloride is added to a one-neck vial (25ml), then water (5ml) is added and sodium carbonate is dropped to pH=9~10 and stirred for 30min. The mixture is extracted by ethyl acetate, washed and evaporated under reduced pressure to remove solvent and obtain 2-(4-chlorophenyl)-4-(3-tetrahydropyrrolemethyl)-thieno[2,3-d]pyridazinyl-7- formamide (70mg). MS (ESI): 373(M+1)

Example 7: 2-(4-chlorophenyl)-4-(3-tetrahydrofuranmethyl)-thieno[2,3-d]pyridazinyl-7-formamide

Etapa 1:[092]

Step 1:

[093] DMPU (225ml), FeCl3 (0.75g) and CuCl (0.3g) are added to 3-bromomethyltetrahydrofuran (24.75g, 0.138mol) and then Et2Zn (106.8ml) is slowly dripped into 40~45°C for 45 minutes to obtain a zinc reagent.

[094] THF (810 ml) and PdCl2(dppf) (5.09g) are added to 4-chloro-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (30g) and then the zinc reagent is dropped into the THF solution at 45°C for 4 h. The reaction mixture is poured into saturated brine, filtered after stirring for 15 minutes and placed for layer separation. The aqueous phase is extracted with THF (500 ml, 2 times). The organic phase is combined, washed with saturated brine (500ml, 3 times), dried with anhydrous Na 2 SO 4 , and evaporated under reduced pressure to remove solvent and obtain 4-(3-tetrahydropyranomethyl)-2-(4-chlorophenyl) )-thieno[2,3-d]pyridazinyl-7-ethyl (25 g). MS (ESI): 403(M+1)

Step 2:

[095] 4-(3-Tetrahydrofuranmethyl)-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl formate (3g), 1,4-dioxane (5ml) and NH3.H2O (5 ml) are added to a sealed tube (25 ml) and heated to 80°C overnight. The reaction is cooled to room temperature and transferred to a separating funnel the following day and ethyl acetate added, vibrated, placed for layer separation. The aqueous layer is re-extracted with ethyl acetate 2 times. The organic phase is combined together and adjusted with 1M HCl solution to pH~3, then washed with saturated brine to pH=7, dried with anhydrous Na2SO4 and filtered. The filtered liquid is purified with silica gel by chromatography to obtain a solid of 2-(4-chlorophenyl)-4-(3-tetrahydrofuranmethyl)-thieno[2,3-d]pyridazinyl-7-formamide (2 g). ). MS (ESI): 374(M+1)

Example 8: 2-(4-chlorophenyl)-4-(3-tetrahydrothiophenomethyl)-thieno[2,3-d]pyridazinyl-7-formamide

Etapa 1:[096]

Step 1:

[097] DMPU (225ml), FeCl3 (0.75 g) and CuCl (0.3 g) are added to 3-bromomethyl tetrahydrothiophene (24.75g, 0.138mol) and then Et2Zn (106.8ml) it is slowly dripped at 40~45°C for 45 minutes to obtain a zinc reagent.

[098] 4-Chloro-2-(4-chlorophenyl)-thieno[2,3-d] pyridazinyl-7-ethyl format (30g), THF (810 ml) and PdCl2(dppf) (5.09 g) are added and then the zinc reagent is dropped into the THF solution at 45°C for 4 h. The reaction mixture is poured into saturated brine, filtered after stirring for 15 minutes and placed for layer separation. The aqueous phase is extracted with THF (500 ml, 2 times). The organic phase is combined, washed with saturated brine (500ml, 3 times), dried with anhydrous Na2SO4, and evaporated under reduced pressure to remove solvent and obtain 4-(3-tetrahydrothiophenomethyl)-2-(4-chlorophenyl) )-thieno[2,3-d]pyridazinyl-7-ethyl (25 g). MS (ESI): 419(M+1)

Step 2:

[099]4-(3-tetrahydrothiophenomethyl)-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (3g), 1,4-dioxane (5ml) and NH 3 . H2O (5ml) is added to a sealed tube (25ml) and heated to 80°C overnight. The reaction mixture is cooled to room temperature and transferred to a separating funnel the next day, there is also addition of ethyl acetate, stirring, to finally be placed for layer separation. The aqueous layer is re-extracted with ethyl acetate 2 times. The organic phase is combined and adjusted with 1M HCl solution to pH~3, then washed with saturated brine until pH=7, dried with anhydrous Na2SO4 and filtered. The filtered liquid is purified with silica gel by chromatography to obtain a solid of 2-(4-chlorophenyl)-4-(3-tetrahydrothiophene methyl)thieno[2,3-d]pyridazinyl-7-formamide (2 g). ). MS (ESI): 389(M+1)

Example 9 2-(4-chlorophenyl)-4-(3-pyridinemethyl)-thieno[2,3-d]pyridazinyl-7-formamide

Etapa 1:[100]

Step 1:

[101] DMPU (225ml), FeCl3 (0.75 g) and CuCl (0.3 g) are added to 3-bromomethylpyridine (24.75g, 0.138mol) and then Et2Zn (106.8ml) is slowly dripped off at 40~45°C for 45 minutes to obtain a zinc reagent.

[102] THF (810ml) and PdCl2(dppf) (5.09g) are added to 4-chloro-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (30g) and, then the zinc reagent is dropped into the THF solution at 45°C for 4h. The reaction mixture is poured into saturated brine, filtered after stirring for 15 minutes and placed for liquid separation. The aqueous phase is extracted with THF (500 ml, 2 times). The organic phase is combined, washed with saturated brine (500ml, 3 times), dried with anhydrous Na2SO4, and evaporated under reduced pressure to remove solvent and obtain 4-(3-pyridinemethyl)-2-(4-chlorophenyl)- thieno[2,3-d]pyridazinyl-7-ethyl (25 g). MS (ESI): 410(M+1)

Step 2:

[103] 4-(3-pyridinemethyl)-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (3g), 1,4-dioxane (5ml) and NH3.H2O ( 5ml) are added to a sealed tube (25ml) and heated to 80°C overnight. The reaction mixture is cooled to room temperature and transferred to a separating funnel the next day, there is also addition of ethyl acetate, stirring, to finally be placed for layer separation. The aqueous layer is re-extracted with ethyl acetate 2 times. The organic phase is combined and adjusted with 1M HCl solution to pH~3, then washed with saturated brine until pH=7, dried with anhydrous Na2SO4 and filtered. The filtered liquid is purified with silica gel by chromatography to obtain a solid of 2-(4-chlorophenyl)-4-(3-pyridinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide (2 g). MS (ESI): 381 (M+1)

Example 10: 2-(4-chlorophenyl)-4-(3-α-pyranomethyl)-thieno[2,3-d] pyridazinyl-7-formamide

Etapa 1:[104]

Step 1:

[105]DMPU (225ml), FeCl3 (0.75 g) and CuCl (0.3 g) are added to 3-bromomethylpyran (24.75g, 0.138mol) and then Et2Zn (106.8ml) is slowly dropped in at 40~45°C for 45 minutes to obtain a zinc reagent.

[106] THF (810 ml) and PdCl2(dppf) (5.09 g) are added to 4-chloro-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (30g) and then the zinc reagent is dropped into the THF solution at 45°C for 4 h. The reaction mixture is poured into saturated brine, filtered after stirring for 15 minutes and placed for layer separation. The aqueous phase is extracted with THF (500 ml, 2 times). The organic phase is combined, washed with saturated brine (500ml, 3 times), dried with anhydrous Na2SO4, and evaporated under reduced pressure to remove solvent and obtain 4-(3-α-pyranomethyl)-2-(4-chlorophenyl) )-thieno[2,3-d]pyridazinyl-7-ethyl (25 g). MS (ESI): 412(M+1)

Step 2:

[107] 4-(3-α-pyranomethyl)-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (3g), 1,4-dioxane (5ml) and NH3. H2O (5ml) is added to a sealed tube (25ml) and heated to 80°C overnight. The reaction mixture is cooled to room temperature and transferred to a separating funnel the next day, there is also addition of ethyl acetate, stirring, to finally be placed for layer separation. The aqueous layer is re-extracted with ethyl acetate 2 times. The organic phase is combined and adjusted with 1M HCl solution to pH~3, then washed with saturated brine until pH=7, dried with anhydrous Na2SO4 and filtered. The filtered liquid is purified with silica gel by chromatography to obtain a solid of 2-(4-chlorophenyl)-4-(3-α-pyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide (2 g). ). MS (ESI): 383(M+1)

Example 11: 2-(4-chlorophenyl)-4-(3-α-thiapyranomethyl)-thieno[2,3-d] pyridazinyl-7-formamide

Etapa 1:[108]

Step 1:

[109] DMPU (225ml), FeCl3 (0.75g) and CuCl (0.3g) are added to 3-bromomethylthiopyran (24.75g, 0.138mol) and then Et2Zn (106.8ml) is slowly dripped off at 40~45˚ dropped at 40~45°C for 45 minutes to obtain a zinc reagent.

[110] THF (810 ml) and PdCl2(dppf) (5.09 g) are added to 4-chloro-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl formate ( 30g) and then the zinc reagent is dropped into the THF solution at 45°C for 4 h. The reaction mixture is poured into saturated brine, filtered after stirring for 15 minutes and placed for layer separation. The aqueous phase is extracted with THF (500 ml, 2 times). The organic phase is combined, washed with saturated brine (500ml, 3 times), dried with anhydrous Na 2 SO 4 , and evaporated under reduced pressure to remove solvent and obtain 4-(3-α-thiopyranomethyl)-2-(4-formate chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (25 g). MS (ESI): 428(M+1)

Step 2:

[111] 4-(3-α-thiopyranomethyl)-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl formate (3g), 1,4-dioxane (5ml) and NH3.H2O (5 ml) are added to a sealed tube (25 ml) and heated to 80°C overnight. The reaction mixture is cooled to room temperature and transferred to a separating funnel the next day, and ethyl acetate is also added, stirring, to finally be placed for layer separation. The aqueous layer is re-extracted with ethyl acetate 2 times. The organic phase is combined and adjusted with 1M HCl solution to pH~3, then washed with saturated brine until pH=7, dried with anhydrous Na2SO4 and filtered. The filtered liquid is purified with silica gel by chromatography to obtain a solid of 2-(4-chlorophenyl)-4-(3-α-thiopyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide (2 g). ). MS (ESI): 399(M+1)

Example 12: 2-(4-chlorophenyl)-4-(2-pyridinemethyl)-thieno[2,3-d]pyridazinyl-7-formamide

Etapa 1:[112]

Step 1:

[113] DMPU (225ml), FeCl3 (0.75 g) and CuCl (0.3 g) are added to 2-bromomethylpyridine (24.75g, 0.138mol) and then Et2Zn (106.8ml) is slowly dripped off at 40~45°C for 45 minutes to obtain a zinc reagent.

[114] THF (810 ml) and PdCl2(dppf) (5.09 g) are added to 4-chloro-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (30g) and then the zinc reagent is dropped into the THF solution at 45°C for 4 hours. The reaction mixture is poured into saturated brine, filtered after stirring for 15 minutes, and placed for layer separation. The aqueous phase is extracted with THF (500 ml, 2 times). The organic phase is combined, washed with saturated brine (500ml, 3 times), dried with anhydrous Na2SO4, and evaporated under reduced pressure to remove solvent and obtain 4-(2-pyridinemethyl)-2-(4-chlorophenyl)- thieno[2,3-d]pyridazinyl-7-ethyl (25 g). MS (ESI): 410(M+1)

Step 2:

[115] 4-(2-pyridinemethyl)-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (3g), 1,4-dioxane (5ml) and NH3.H2O ( 5ml) are added to a sealed tube (25ml) and heated to 80°C overnight. The reaction mixture is cooled to room temperature and transferred to a separating funnel the next day, there is also addition of ethyl acetate, stirring, to finally be placed for layer separation. The aqueous layer is re-extracted with ethyl acetate 2 times. The organic phase is combined and adjusted with 1M HCl solution to pH~3, then washed with saturated brine until pH=7, dried with anhydrous Na2SO4 and filtered. The filtered liquid is purified with silica gel by chromatography to obtain a solid of 2-(4-chlorophenyl)-4-(2-pyridinemethyl)thieno[2,3-d]pyridazinyl-7-formamide (2 g). MS (ESI): 381 (M+1)

Example 13: 2-(4-chlorophenyl)-4-(4-pyridinemethyl)-thieno[2,3-d]pyridazinyl-7-formamide

Etapa 1:[116]

Step 1:

[117] DMPU (225ml), FeCl3 (0.75g) and CuCl (0.3g) are added to 4-bromomethylpyridine (24.75g, 0.138mol) and then Et2Zn (106.8ml) is slowly dropped at 40°C ~45°C for 45 minutes to obtain a zinc reagent.

[118] THF (810ml) and PdCl2(dppf) (5.09g) are added to 4-chloro-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (30g) and, then the zinc reagent is dropped into the THF solution at 45°C for 4 h. The reaction mixture is poured into saturated brine, filtered after stirring for 15 minutes and placed for layer separation. The aqueous phase is extracted with THF (500 ml, 2 times). The organic phase is combined, washed with saturated brine (500ml, 3 times), dried with anhydrous Na2SO4, and evaporated under reduced pressure to remove solvent and obtain 4-(4-pyridinemethyl)-2-(4-chlorophenyl)- thieno[2,3-d]pyridazinyl-7-ethyl (25 g). MS (ESI): 410(M+1)

Step 2:

[119] 4-(4-pyridinemethyl)-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (3g), 1,4-dioxane (5ml) and NH3.H2O ( 5ml) are added to a sealed tube (25ml) and heated to 80°C overnight. The reaction mixture is cooled to room temperature and transferred to a separating funnel the next day, there is also addition of ethyl acetate, stirring, to finally be placed for layer separation. The aqueous layer is re-extracted with ethyl acetate 2 times. The organic phase is combined and adjusted with 1M HCl solution to pH~3, then washed with saturated brine until pH=7, dried with anhydrous Na2SO4 and filtered. The filtered liquid is purified with silica gel by chromatography to obtain a solid of 2-(4-chlorophenyl)-4-(4-pyridinemethyl)-thieno[2,3-d]pyridazinyl-7-formamide (2 g). MS (ESI): 381 (M+1)

Example 14: 2-(4-chlorophenyl)-4-(3-pyrrolemethyl)-thieno[2,3-d] pyridazinyl-7-formamide

Etapa 1:[120]

Step 1:

[121] DMPU (225ml), FeCl3 (0.75 g) and CuCl (0.3 g) are added to 3-bromomethylpyrrole (24.75g, 0.138mol) and then Et2Zn (106.8ml) is slowly dripped off at 40~45˚C for 45 minutes to obtain a zinc reagent.

[122] THF (810ml) and PdCl2(dppf) (5.09g) are added to 4-chloro-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (30g) and, then the zinc reagent is dropped into the THF solution at 45°C for 4 h. The reaction mixture is poured into saturated brine, filtered after stirring for 15 minutes and placed for layer separation. The aqueous phase is extracted with THF (500 ml, 2 times). The organic phase is combined, washed with saturated brine (500ml, 3 times), dried with anhydrous Na2SO4, and evaporated under reduced pressure to remove solvent and obtain 4-(3-pyrrolemethyl)-2-(4-chlorophenyl)- thieno[2,3-d]pyridazinyl-7-ethyl (25 g). MS (ESI): 398(M+1)

Step 2:

[123] 4-(3-pyrrolemethyl)-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (3g), 1,4-dioxane (5ml) and NH3.H2O ( 5ml) is added to a sealed tube (25ml) and heated to 80˚C overnight. The reaction mixture is cooled to room temperature and transferred to a separating funnel the next day, there is also addition of ethyl acetate, stirring, to finally be placed for layer separation. The aqueous layer is re-extracted with ethyl acetate 2 times. The organic phase is combined and adjusted with 1M HCl solution to pH≈3, then washed with saturated brine until pH=7, dried with anhydrous Na2SO4 and filtered. The filtered liquid is purified with silica gel by chromatography to obtain a solid of 2-(4-chlorophenyl)-4-(3-pyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-formamide (2 g). MS (ESI): 369(M+1)

Example 15: 2-(4-chlorophenyl)-4-(3-furanmethyl)-thieno[2,3-d]pyridazinyl-7-formamide

Etapa 1:[124]

Step 1:

[125] DMPU (225ml), FeCl3 (0.75 g) and CuCl (0.3 g) are added to 3-bromomethylfuran (24.75g, 0.138mol) and then Et2Zn (106.8ml) is slowly dripped off at 40~45°C for 45 minutes to obtain a zinc reagent.

[126] THF (810ml) and PdCl2(dppf) (5.09g) are added to 4-chloro-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (30g) and, then the zinc reagent is added dropwise to the THF solution at 45°C for 4 h. The reaction mixture is poured into saturated brine, filtered after stirring for 15 minutes and placed for layer separation. The aqueous phase is extracted with THF (500 ml, 2 times). The organic phase is combined, washed with saturated brine (500ml, 3 times), and dried with anhydrous Na2SO4, and evaporated under reduced pressure to remove solvent and obtain 4-(3-furanomethyl)-2-(4-chlorophenyl) )-thieno[2,3-d]pyridazinyl-7-ethyl (25 g). MS (ESI): 399(M+1)

Step 2:

[127] 4-(3-furanomethyl)-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl formate (3g), 1,4-dioxane (5 ml) and NH 3 . H2O (5ml) is added to a sealed tube (25ml) and heated to 80°C overnight. The reaction mixture is cooled to room temperature and transferred to a separating funnel the next day, there is also addition of ethyl acetate, stirring, to finally be placed for layer separation. The aqueous layer is re-extracted with ethyl acetate 2 times. The organic phase is combined and adjusted with 1M HCl solution to pH~3, then washed with saturated brine until pH=7, dried with anhydrous Na2SO4 and filtered. The filtered liquid is purified with silica gel by chromatography to obtain a solid of 2-(4-chlorophenyl)-4-(3-furanomethyl)-thieno[2,3-d]pyridazinyl-7-formamide (2 g). MS (ESI): 370(M+1)

Example 16: 2-(4-chlorophenyl)-4-(3-thiaphenomethyl)-thieno[2,3-d] pyridazinyl-7-formamide

Etapa 1:[128]

Step 1:

[129] DMPU (225ml), FeCl3 (0.75 g) and CuCl (0.3 g) are added to 3-bromomethylthiophene (24.75g, 0.138mol) and then Et2Zn (106.8ml) is slowly dripped off at 40~45°C for 45 minutes to obtain a zinc reagent.

[130] THF (810ml) and PdCl2(dppf) (5.09g) are added to 4-chloro-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (30g) and, then the zinc reagent is dropped into the THF solution at 45°C for 4 h. The reaction mixture is poured into saturated brine, filtered after stirring for 15 minutes and placed for layer separation. The aqueous phase is extracted with THF (500 ml, 2 times). The organic phase is combined, washed with saturated brine (500ml, 3 times), dried with anhydrous Na2SO4, and evaporated under reduced pressure to remove solvent and obtain 4-(3-thiophenomethyl)-2-(4-chlorophenyl)- thieno[2,3-d]pyridazinyl-7-ethyl (25 g). MS (ESI): 415(M+1)

Step 2:

[131] 4-(3-thiophenomethyl)-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (3g), 1,4-dioxane (5ml) and NH3.H2O ( 5ml) are added to a sealed tube (25ml) and heated to 80°C overnight. The reaction mixture is cooled to room temperature and transferred to a separating funnel the next day, there is also addition of ethyl acetate, stirring, to finally be placed for layer separation. The aqueous layer is re-extracted with ethyl acetate 2 times. The organic phase is combined and adjusted with 1M HCl solution to pH~3, then washed with saturated brine until pH=7, dried with anhydrous Na2SO4 and filtered. The filtered liquid is purified with silica gel by chromatography to obtain a solid of 2-(4-chlorophenyl)-4-(3-thiophenomethyl)-thieno[2,3-d]pyridazinyl-7-formamide (2 g). MS (ESI): 386(M+1)

Example 17: 2-(4-chlorophenyl)-4-(2-pyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-formamide

Etapa 1:[132]

Step 1:

[133] DMPU (225ml), FeCl3 (0.75g) and CuCl (0.3g) are added to 2-bromomethylpyrrole (24.75g, 0.138mol) and then Et2Zn (106.8ml) is slowly dripped off at 40~45°C for 45 minutes to obtain a zinc reagent.

[134] THF (810ml) and PdCl2(dppf) (5.09g) are added to 4-chloro-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (30g) and, then the zinc reagent is dropped into the THF solution at 45°C for 4 h. The reaction mixture is poured into saturated brine, filtered after stirring for 15 minutes and placed for layer separation. The aqueous phase is extracted with THF (500 ml, 2 times). The organic phase is combined, washed with saturated brine (500ml, 3 times), dried with anhydrous Na2SO4, and evaporated under reduced pressure to remove solvent and obtain 4-(2-pyrrolemethyl)-2-(4-chlorophenyl)- thieno[2,3-d]pyridazinyl-7-ethyl (25 g). MS (ESI): 398(M+1)

Step 2:

[135] 4-(2-pyrrolemethyl)-2-(4-chlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (3g), 1,4-dioxane (5 ml) and NH3.H2O ( 5ml) are added to a sealed tube (25ml) and heated to 80°C overnight. The reaction mixture is cooled to room temperature and transferred to a separating funnel the next day, there is also addition of ethyl acetate, stirring, to finally be placed for layer separation. The aqueous layer is re-extracted with ethyl acetate 2 times. The organic phase is combined and adjusted with 1M HCl solution to pH~3, then washed with saturated brine until pH=7, dried with anhydrous Na2SO4 and filtered. The filtered liquid is purified with silica gel by chromatography to obtain a solid of 2-(4-chlorophenyl)-4-(2-pyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-formamide (2 g). MS (ESI): 369(M+1)

Example 18: 2-(3,5-dichlorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide

Etapa 1:[136]

Step 1:

[137] 5-bromo-thiophene-3-ethyl (10.5g), 3,5-dichlorobenzene boronic acid (6g), Pd[P(Ph)3]4 (1.5g), sodium carbonate (7, 5g) and a mixture (347ml) of toluene:water:EtOH (4:2:1, v/v) are successively added to a three-neck flask (500ml) and heated to reflux for 3 h. The reaction is tracked by TLC. The reaction mixture is cooled to room temperature after the reaction and placed for layer separation. The aqueous phase is extracted with toluene (35ml, 2 times). The organic phase is combined and washed with saturated brine until pH=7, dried with anhydrous sodium sulphate overnight and filtered the next day, and evaporated under reduced pressure to remove solvent and obtain a pale yellow viscous liquid, placed for solid condensation, and recrystallized from absolute EtOH to obtain a crystal of 5-(3,5-dichlorophenyl)-3-thiophene-ethyl (8.6g).

Step 2:

[138] Preparation of LDA: THF (252.6ml) and N,N-diisopropylamine (79ml) are added in a three-neck flask (1000ml) under argon, and n-Buli (302.8ml, 1.6M in hexane) ) is added into a constant pressure funnel (500ml) and dropped when the internal temperature is below -20°C, as the reaction is intensely exothermic, the internal temperature is maintained between -20°C-30°C by controlling the speed addition. After addition, the reaction mixture is naturally warmed to room temperature and then directly used for the condensation reaction to follow.

[139] Condensation Reaction: 5-(3,5-dichlorophenyl)thiophene-3-ethyl (28.7g), THF (1084ml) and diethyl oxalate (29.7ml) are added in a four-neck flask (2000ml) connecting with a mechanical stirring device, a 500ml constant pressure funnel and a temperature probe. The above mixture is stirred at room temperature and dissolved to obtain a clear, pale yellow liquid. The prepared LDA solution is transferred to a constant pressure funnel under argon, cooled, and then the LDA is dropped into the flask when the internal temperature is below -78°C, maintaining this temperature and controlling the addition rate . After addition, the reaction is tracked by TLC. HCl solution (2.2M) is added to adjust pH~3 after the reaction, and the color of the reaction mixture is changed from reddish-brown to orange. The temperature is raised to about 0°C, solid NaCl is then added and dissolved under stirring and then placed for layer separation. The aqueous phase is re-extracted with THF (143.5ml, 2 times). The organic phase is combined and washed with saturated brine twice and then adjusted to pH=8 with sodium carbonate solution; finally, washed with saturated brine until pH=7, dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove solvent and obtain a pale yellow viscous fluid, brought to room temperature and gradually condensed to solid, recrystallized by EtOH and obtain a pure product of 5-(3,5-dichlorophenyl)-2-ethoxyoxalyl-thiophene-3-ethyl formate (orange crystal, 25.5g).

Step 3:

[140] A formate crystal of 5-(3,5-dichlorophenyl)-2-ethoxyoxalyl-thiophene-3-ethyl (3.0g), and absolute ethanol (45ml) are added to a reaction flask (100ml), stirred at room temperature to obtain a yellow suspension. Hydrazine hydrate (0.75ml) is added to a constant pressure funnel under stirring for 10 minutes and then dropped into the vial. The yellow suspension is dissolved to a clear liquid and heated to 70°C to gradually precipitate yellow solids in the flask with increasing temperature, and the reaction liquid becomes increasingly viscous, is held for 1h and then cooled to room temperature, filtered to obtain a pistachio green solid, the solid is respectively washed with a mixture of hexane/dichloromethane (1:1)(15ml, 2 times) and methanol/dichloromethane (1:1)(15ml, 2 times) ) and dried under reduced pressure to obtain 2-(3,5-dichlorophenyl)-4-oxo-4,5-dihydro-thieno[2,3-d]pyridazine-7-ethyl formate (2.75g) .

Step 4:

[141] 2-(3,5-dichlorophenyl)-4-oxo-4,5-dihydro-thieno[2,3-d]pyridazine-7-ethyl (1.5g) and phosphorus oxychloride (22.5ml) are added to a three-neck flask (100ml), heated to 90°C for 3 h, and gradually dissolved to obtain a dark red-brown solution. After the reaction, the solution is cooled to room temperature and evaporated under reduced pressure to remove solvent and obtain a viscous chocolate-brown fluid. THF and saturated brine are added under stirring, then yellow solids are precipitated, filtered, placed for layer separation, and re-extracted and adjusted to pH=9 with dilute sodium carbonate solution after the organic phase is combined and then washed with saturated brine until pH=7, and dried with anhydrous sodium sulfate, filtered, decolorized with activated carbon at reflux to obtain a pale yellow-green liquid, the liquid is evaporated under reduced pressure to remove solvent and obtain the 4- chloro-2-(3,5-dichlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (light green flocculent solid, 1.0g).

Step 5:

[142] DMPU (5ml), FeCl3 (0.017g) and CuCl (0.007g) are added to N-Boc-3-bromomethylpiperidine (0.55g) and then Et2Zn (2.5ml) is slowly dropped to 40~ 45°C for 45 minutes to obtain a zinc reagent.

[143] THF (18ml) and PdCl2(dppf) (0.12g) are added to 4-chloro-2-(3,5-dichlorophenyl)-thieno[2,3-d]pyridazinyl-7-ethyl (30g) and then the zinc reagent is dropped into the THF solution at 45°C for 4 h. The reaction mixture is poured into saturated brine, filtered after stirring for 15 minutes and placed for layer separation. The aqueous phase is extracted with THF (80 ml, 2 times). The organic phase is combined, washed with saturated brine (80ml, 3 times), dried over anhydrous Na 2 SO 4 , and evaporated under reduced pressure to remove solvent and obtain 2-(3,5-dichlorophenyl)-4-(N-Boc -3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-ethyl (0.5 g).

Step 6:

[144] 2-(3,5-dichlorophenyl)-4-(N-Boc-3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-ethyl (0.5g), 1,4-dioxane ( 1.0ml) and NH3.H2O (5ml) are added to a sealed tube (5ml) and heated at 80°C overnight. The reaction mixture is cooled to room temperature and transferred to a separating funnel the following day, and ethyl acetate added, vibrated, placed for layer separation. The water layer is re-extracted with ethyl acetate 2 times. The organic phase is combined and adjusted to pH~3 with 1M HCl solution and then washed with saturated brine until pH=7, dried with anhydrous sodium sulfate and filtered. The filtered liquid is purified along with silica gel by flash chromatography to obtain a solid of 2(3,5-dichlorophenyl)-4-(N-Boc-3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7 -formamide (0.3g).

Step 7:

[145] 2(3,5-dichlorophenyl)-4-(N-Boc-3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide (200g) and ethyl acetate (4ml) are added to a one-mouth vial (25ml) and dissolved into a clear pale yellow solution. HCl solution (4ml, 3M) is added and changed to a white suspension, and heated to 30°C for 1 h and the white suspension is changed to clear. The reaction is tracked across the plate; and evaporated under reduced pressure after the reaction to remove solvent to obtain a solid of 2-(3,5-dichlorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide hydrochloride ( 100mg).

Step 8:

[146] 2-(3,5-Dichlorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide hydrochloride (100 mg) is added to a one-neck flask (25ml) ), then addition of water (5ml) and the sodium carbonate is dropped to pH=9~10 under stirring for 30min. The mixture is extracted by ethyl acetate, washed with water and evaporated under reduced pressure to remove solvent to obtain 2-(3,5-dichlorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl- 7- formamide (70 mg). MS (ESI): 421 (M+1)

Example 19: Preparation of Pharmaceutical Formulations

[147]

[148] Compound II is added to a tank according to the formulation, and water for injection (about 200,000ml) is added, and dissolved completely. Sodium chloride is then added according to the formulation and then continued to add enough sodium chloride after it has completely dissolved. The pH is adjusted to 4.0~5.0. Activated carbon (250g) is added for 30 minutes before being removed by decarbonising the filter. The mixture is then filled into 250ml bottles after precision filtration with a Titanium Bar. The injection is prepared after sterilizing water at 115°C for 30 minutes. 2. Pills

[149]

[150]CompoundXXXIII, starch and hydroxypropyl cellulose are added to a fluidized bed trough, and heated to 38°C~45°C by opening the main air to premix the material for 5 minutes. Suitable polyvidone K30 solution (5%) is nebulized to granulate, the material is controlled to 55°C~60°C and dried for 10 minutes, mixed with sodium carboxymethyl starch and magnesium stearate to form tablets after granulation. 3. Capsules

[151]

[152] Compound XXXXIV, lactose, sodium carboxymethyl starch and colloidal silicon dioxide are added to a blender according to the formulation and mixed for 60 minutes to make it homogeneous. Magnesium stearate is then added according to the formulation and mixed for 10 minutes, then dispensed into a general gelatin plastic shell.

Tabela 2 Os efeitos da inibição do crescimento dos compostos no cancer de colon de camundongo S180

Observação: ip: administração de injeçãointraperitoneal. Tabela 3 A eficácia do composto em tratar tumores transplantados de câncer de cólon humano HT-99 em camundongos nus

Observações: d0: momento da administração para a primeira vez; dn: o 17o. dia após a administração; RTV: volume relativo do tumor; Grupo de controle: n=10; Grupo de tratamento: n=6; ip:administração de injeçãointraperitoneal iv: administração de injeção intravenosa GCT é um medicamento de controle: Gemcitabina ADR é um medicamento de controle: Adriamicina CPT-11 é um medicamento de controle: Irinotecano[153] Some of the above compounds are tested in vitro and in vivo for their antitumor activities. Among these tests, cytotoxicity is tested in vitro using the SRB and MTT methods for 72h. The specific activity data are summarized in Table 1. The growth-inhibitory effect of the compound on S180 mouse sarcoma is summarized in Table 2. The efficacy of the compounds in treating HT-99 human colon cancer transplanted tumors in nude mice is summarized in Table 3. Table 1 Anticancer Activity of Compound IC50(μM) in Vitro

Table 2 The effects of growth inhibition of compounds on S180 mouse colon cancer

Note: ip: intraperitoneal injection administration. Table 3 The efficacy of the compound in treating HT-99 human colon cancer transplant tumors in nude mice

Notes: d0: time of administration for the first time; dn: the 17th. day after administration; RTV: relative tumor volume; Control group: n=10; Treatment group: n=6; ip: intraperitoneal injection administration iv: intravenous injection administration GCT is a control drug: Gemcitabine ADR is a control drug: Adriamycin CPT-11 is a control drug: Irinotecan

[154] It can be shown from the above tables that the compounds of the present invention not only have certain antitumor effects, and can also enhance the antitumor efficacy of cytotoxic antitumor agents such as Gemcitabine, CPT-11, ADR and so on. .

[155] While the present invention has been described in connection with the above embodiments, it should be understood that the present invention is not limited to such preferred embodiments and procedures set forth above. The materializations and procedures were chosen and described in order to better explain the principles of the invention and its practical application, so as to allow others skilled in the art how to better use the invention.

Claims (12)

1- A compound of formula (I), its pharmaceutically acceptable salt, characterized in that it comprises the formula:

where, R1 and R2 are independently H or C1-4 alkyl; R3 is a 5- or 6-membered saturated or unsaturated ring containing N, S or O; - R4 is a halophenyl monosubstituted or disubstituted in any position. A compound, its pharmaceutically acceptable salt, according to claim 1, characterized in that R1=R2=H. A compound, pharmaceutically acceptable salt thereof, according to claim 1, characterized in that R 3 is hexahydropyridinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolidinyl, tetrahydrofuranyl or tetrahydrothienyl. A compound, pharmaceutically acceptable salt thereof, according to claim 3, characterized in that R 3 is hexahydropyridinyl. A compound, its pharmaceutically acceptable salt, according to claim 1, characterized in that R 4 is a monosubstituted halophenyl

, where X represents F, Cl, Br, I. 6. A compound, pharmaceutically acceptable salt thereof, according to claim 1, wherein R3 is pyridinyl, α-pyranyl, Y-pyranyl, α-thiopyranyl, y-thiopyranyl, pyrrolidinyl, furanyl, or thienyl. 7. Compound, its pharmaceutically acceptable salt, according to claim 1, characterized in that the compounds of formula (I) are selected from: - 2-(4-fluorophenyl)-4-(3-piperidinomethyl)-thieno[2 ,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d] pyridazinyl-7-formamide; - 2-(4-bromophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d] pyridazinyl-7-formamide; - 2-(4-fluorophenyl)-4-(3-tetrahydropyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(3-tetrahydropyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-bromophenyl)-4-(3-tetrahydropyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-fluorophenyl)-4-(3-tetrahydrothiapyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(3-tetrahydrothiapyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-bromophenyl)-4-(3-tetrahydrothiapyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(2-piperidinomethyl)-thieno[2,3-d] pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(4-piperidinomethyl)-thieno[2,3-d] pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(S-3-piperidinomethyl)-thieno[2,3-d] pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(R-3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl-formamide; - 2-(4-chlorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl-7-formamide; - 2-(4-chlorophenyl)-4-(3-tetrahydrothiapyranomethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl-formamide; - 2-(4-chlorophenyl)-4-(3-tetrahydrothiapyranomethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl-7-formamide; - 2-(4-chlorophenyl)-4-(3-tetrahydropyranomethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl-formamide; - 2-(4-chlorophenyl)-4-(3-tetrahydropyranomethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl-7-formamide; - 2-(4-fluorophenyl)-4-(3-pyrrolidinomethyl)-thieno[2,3-d] pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(3-pyrrolidinomethyl)-thieno[2,3-d] pyridazinyl-7-formamide; - 2-(4-bromophenyl)-4-(3-pyrrolidinomethyl)-thieno[2,3-d] pyridazinyl-7-formamide; - 2-(4-fluorophenyl)-4-(3-tetrahydrofuranmethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(3-tetrahydrofuranmethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-bromophenyl)-4-(3-tetrahydrofuranmethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-fluorophenyl)-4-(3-tetrahydrothiophenomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(3-tetrahydrothiophenomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-bromophenyl)-4-(3-tetrahydrothiophenomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(3-pyrrolidinomethyl)-thieno[2,3-d] pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(S-3-pyrrolidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(R-3-pyrrolidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(3-pyrrolidinomethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl-formamide; - 2-(4-chlorophenyl)-4-(3-pyrrolidinomethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl-formamide; - 2-(4-chlorophenyl)-4-(3-tetrahydrothiophenomethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl-formamide; - 2-(4-chlorophenyl)-4-(3-tetrahydrothiophenomethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethylformamide; - 2-(4-chlorophenyl)-4-(3-tetrahydrofuranmethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl-formamide; - 2-(4-chlorophenyl)-4-(3-tetrahydrofuranmethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl-formamide; - 2-(4-fluorophenyl)-4-(3-pyridinemethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(3-pyridinemethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-bromophenyl)-4-(3-pyridinemethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-fluorophenyl)-4-(3-α-pyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(3-α-pyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-bromophenyl)-4-(3-α-pyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-fluorophenyl)-4-(3-α-thiopyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(3-α-thiopyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-bromophenyl)-4-(3-α-thiopyranomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(2-pyridinemethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(4-pyridinemethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(3-pyridinemethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide; - 2-(4-chlorophenyl)-4-(3-pyridinemethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide; - 2-(4-chlorophenyl)-4-(3-thiopyranylmethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide; - 2-(4-chlorophenyl)-4-(3-thiopyranylmethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide; - 2-(4-chlorophenyl)-4-(3-pyranomethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide; - 2-(4-chlorophenyl)-4-(3-pyranomethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide; - 2-(4-fluorophenyl)-4-(3-pyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(3-pyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-bromophenyl)-4-(3-pyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-fluorophenyl)-4-(3-furanomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(3-furanomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-bromophenyl)-4-(3-furanomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-fluorophenyl)-4-(3-thiaphenomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(3-thiaphenomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-bromophenyl)-4-(3-thiaphenomethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(2-pyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-formamide; - 2-(4-chlorophenyl)-4-(3-pyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide; - 2-(4-chlorophenyl)-4-(3-pyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide; - 2-(4-chlorophenyl)-4-(3-thiaphenomethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide; - 2-(4-chlorophenyl)-4-(3-thiaphenomethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide; - 2-(4-chlorophenyl)-4-(3-furanomethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide; - 2-(4-chlorophenyl)-4-(3-furanomethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide; - 2-(3,5-dichlorophenyl)-4-(3-piperidinomethyl)-thieno[2,3-d]pyridazinyl-7-formamide. A pharmaceutical composition characterized in that it comprises a therapeutically effective amount of the compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof obtained from this compound and a pharmaceutically acceptable carrier. 9. Use of the compound, its pharmaceutically acceptable salt, according to any one of claims 1 to 7, characterized in that it is used in the preparation of a medication for the treatment or prophylaxis of tumor diseases, a medication for the treatment or prophylaxis of proliferative diseases, a medication for limiting cell proliferation, and a medication for inhibiting tumors or kinases associated with growth factors. 10. Use according to claim 9, characterized in that said tumor diseases include cervical tumor, head and neck tumor, breast, ovarian, non-small cell lung, pancreas, colon, prostate or other tissues, as well as leukemias and lymphomas, central and peripheral nervous system tumors and other tumors such as melanoma, fibrosarcoma and osteosarcoma. Use according to claim 9, characterized in that said proliferative diseases include autoimmune, inflammatory, neurological and cardiovascular diseases. 12. Process for preparing the compound of formula (I), its pharmaceutically acceptable salt, according to any one of claims 1 to 7, the process characterized in that it comprises the following steps: in the presence of alkalis, the compound of formula A is treated with dialkyl oxalates:

then it is treated with hydrazine to produce the compound of formula B:

the compound of formula B is treated with phosphorus oxychloride to produce the compound of formula C:

the compound of formula C reacts with the compound R3CH2 to produce the compound of formula D,

and then the compound of formula D reacts with NHR1R2, the protecting group on R3 is then removed and treated with an alkali to produce the compounds of formula (I) or pharmaceutically acceptable salts,

where R is a C1-4 alkyl, and R1 and R2 are independently H or C1-4 alkyl respectively; R3 is a 5- or 6-membered saturated or unsaturated ring containing N, S or O;, R4 is a halophenyl monosubstituted or disubstituted at any position.